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1.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361797

RESUMO

Carpesium divaricatum Sieb. & Zucc., a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1ß, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5-2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Citotoxinas/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/classificação , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/classificação , Antineoplásicos Fitogênicos/isolamento & purificação , Asteraceae/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Citotoxinas/química , Citotoxinas/classificação , Citotoxinas/isolamento & purificação , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/química , Plantas Medicinais , Polônia , Cultura Primária de Células , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/classificação , Sesquiterpenos de Germacrano/isolamento & purificação , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
2.
Chin J Nat Med ; 19(7): 528-535, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247776

RESUMO

In this study, three new germacranolide sesquiterpenes (1-3), together with six related known analogues (4-9) were isolated from the whole plant of Carpesium cernuum. Their structures were established by a combination of extensive NMR spectroscopic analysis, HR-ESIMS data, and ECD calculations. The anti-leukemia activities of all compounds towards three cell lines (HEL, KG-1a, and K562) were evaluated in vitro. Compounds 1-3 exhibited moderate cytotoxicity with IC50 values ranging from 1.59 to 5.47 µmol·L-1. Mechanistic studies indicated that 2 induced apoptosis by decreasing anti-apoptotic protein Bcl-2 and activating the caspase family in K562 cells. These results suggest that compound 2 is a potential anti-leukemia agent.


Assuntos
Antineoplásicos Fitogênicos , Asteraceae , Sesquiterpenos de Germacrano/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Compostos Fitoquímicos/farmacologia
3.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33880579

RESUMO

Germacrone (GM) displays a wide range of antitumor, antioxidant and anti­inflammatory effects; however, to the best of our knowledge, the effects of GM on lung cancer cell apoptosis and cell cycle arrest have not been previously reported. The aim of the present study was to investigate discussed the effects of GM on the apoptosis and cycle arrest of lung cancer cells. Cell viability, proliferation and apoptosis were assessed by performing Cell Counting Kit­8, colony formation and TUNEL assays, respectively. Western blotting was performed to detect the expression levels of apoptosis­, cell cycle­ and Akt/MDM2 proto­oncogene (MDM2)/p53 signaling pathway­related proteins. Compared with the control group, 50, 100 and 200 µM GM significantly inhibited lung cancer cell proliferation, but significantly induced cell apoptosis and G1/S cell cycle arrest. GM also significantly altered the expression levels of Akt/MDM2/p53 signaling pathway­related proteins compared with the control group. Administration of Akt activator SC79 significantly reversed GM­mediated antiproliferative, proapoptotic and pro­cell cycle arrest effects in lung cancer cells. Therefore, the results of the present study demonstrated that GM induced lung cancer cell apoptosis and cell cycle arrest via the Akt/MDM2/p53 signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Sesquiterpenos de Germacrano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos
4.
J Environ Sci Health B ; 56(4): 423-430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678144

RESUMO

In this work, we investigated the bioactivities of the essential oil (EO) extracted from the Rhododendron thymifolium and its principal germacrone against Lasioderma serricorne and Tribolium castaneum. The EO was obtained by steam distillation. Germacrone was obtained by cryogenic crystallization. The bioactivity of EO and germacrone was tested via contact and repellent activity assays. The results showed that EO and germacrone possessed contact and repellent activities against two species of insects. EO exhibited obvious contact activity against the L. serricorn adults, larvae and T. castaneum larvae with LD50 values of 29.15 µg/adult, 42.73 µg/larva, 19.65 µg/larva respectively. Germacrone exhibited excellent contact activity against the L. serricorne adults, larvae and the T. castaneum larvae with LD50 values of 17.18 µg/adult, 20.94 µg/larva, 20.93 µg/larva respectively. And at the highest testing concentrations (78.63 and 15.73 nL/cm2), the repellent activity of EO and germacrone on two target insects was comparable to that of the positive control (DEET) after 30 h exposure. In especially, in the treatment of the 120 h after the repellent activity of EO and germacrone against T.castaneum adults and larvae were still very significant and showed the same level percentage repellency as DEET. Meanwhile, germacrone exhibited inhibition of acetylcholinesterase activity with IC50 values of 3%. The results indicated that the EO of R. thymifolium and germacrone had the potential to be developed as natural insecticides and repellents for the control of T. castaneum and L. serricorne.


Assuntos
Inibidores da Colinesterase/farmacologia , Besouros/efeitos dos fármacos , Inseticidas/farmacologia , Óleos Voláteis/farmacologia , Rhododendron/química , Animais , Inibidores da Colinesterase/química , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Inseticidas/química , Dose Letal Mediana , Óleos Voláteis/química , Sesquiterpenos de Germacrano/farmacologia , Tribolium/química , Tribolium/efeitos dos fármacos
5.
BMC Complement Med Ther ; 21(1): 6, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402180

RESUMO

BACKGROUND: Germacrone (GM) is a terpenoid compound which is reported to have anti-inflammatory and anti-oxidative effects. However, its role in treating traumatic brain injury (TBI) remains largely unknown. METHODS: Male C57BL/6 mice were divided into the following groups: control group, TBI group [controlled cortical impact (CCI) model], CCI + 5 mg/kg GM group, CCI + 10 mg/kg GM group and CCI + 20 mg/kg GM group. GM was administered via intraperitoneal injection. The neurological functions (including motor coordination, spatial learning and memory abilities) and brain edema were measured. Nissl staining was used to detect the neuronal apoptosis. Colorimetric assays and enzyme linked immunosorbent assay (ELISA) kits were used to determine the expression levels of oxidative stress markers including myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD), as well as the expressions of inflammatory markers, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). Additionally, protein levels of Nrf2 and p-p65 were detected by Western blot assay. RESULTS: GM significantly ameliorated motor dysfunction, spatial learning and memory deficits of the mice induced by TBI and it also reduced neuronal apoptosis and microglial activation in a dose-dependent manner. Besides, GM treatment reduced neuroinflammation and oxidative stress compared to those in the CCI group in a dose-dependent manner. Furthermore, GM up-regulated the expression of antioxidant protein Nrf2 and inhibited the expression of inflammatory response protein p-p65. CONCLUSIONS: GM is a promising drug to improve the functional recovery after TBI via repressing neuroinflammation and oxidative stress.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Doenças do Sistema Nervoso/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Sesquiterpenos de Germacrano/uso terapêutico , Animais , Encéfalo/metabolismo , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/metabolismo , Curcuma , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Sesquiterpenos de Germacrano/farmacologia , Aprendizagem Espacial/efeitos dos fármacos
6.
Phytochemistry ; 183: 112632, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33360528

RESUMO

Chemical analysis of the aerial parts obtained from a Tunisian specimen of Daucus carota yielded to the isolation of six undescribed polyoxygenated germacranes and one elemanolide, along with one known metabolite. The stereostructures of the undescribed compounds were determined by extensive spectroscopic analysis including 1D and 2D NMR and HR-ESI-MS analysis. Due to their structural similarity with the Plasmodium transmission-blocking agent daucovirgolide G, the isolated metabolites were evaluated for their inhibitory activity on the development of Plasmodium early sporogonic stages. Three compounds proved to inhibit ookinete formation showing a good transmission blocking efficacy, but the low potency exhibited by these compounds when compared to daucovirgolide G further supports the observation that strict structural requirements do exist for the antimalarial activity of germacranolides.


Assuntos
Antimaláricos , Daucus carota , Antimaláricos/farmacologia , Espectroscopia de Ressonância Magnética , Sesquiterpenos de Germacrano/farmacologia
7.
Nat Prod Res ; 35(11): 1887-1892, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31293176

RESUMO

This study was designed to examine the chemical composition and anticholinesterase inhibitory activity of the essential oil of Pseuduvaria macrophylla (Oliv.) Merr. (Annonaceae) from Malaysia. The essential oil was obtained by hydrodistillation and fully analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The analysis led to the identification of thirty-four chemical components that represented 87.7 ± 0.5% of the total oil. The essential oil was found to be rich in germacrene D (21.1 ± 0.4%), bicyclogermacrene (10.5 ± 0.5%), δ-cadinene (5.6 ± 0.2%), α-copaene (5.1 ± 0.3%), and α-cadinol (5.0 ± 0.3%). Anticholinesterase activity was evaluated using Ellman method. The essential oil showed weak inhibitory activity against acetylcholinesterase (I%: 32.5%) and butyrylcholinesterase (I%: 35.4%) assays. Our findings demonstrate that the essential oil could be very useful for the characterization, pharmaceutical and therapeutic applications of the essential oil from Pseuduvaria macrophylla.


Assuntos
Annonaceae/química , Inibidores da Colinesterase/farmacologia , Óleos Voláteis/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Malásia , Óleos Voláteis/química , Sesquiterpenos/farmacologia , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologia
8.
Nat Prod Res ; 35(11): 1914-1918, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31328548

RESUMO

This work evaluated the volatile composition, antioxidant and antiprotozoal activities of the essential oil obtained from leaves of Eugenia gracillima Kiaersk. (EGEO) grown in Brazilian Northeast area (Araripe, Brazil). The volatile compounds of EGEO were analyzed by GC and GC-MS and its chemical composition is mainly composed of sesquiterpene hydrocarbons (91.22%), oxygenated sesquiterpenes (7.45%) and monoterpene (1.01%). The most abundant volatile constituents of the EGEO were germacrene D (16.10%), γ-muurolene (15.60%), bicyclogermacrene (8.53%), germacrene B (7.43%), and Δ-elemene (6.06%). The oil showed weak to moderate antioxidant activity. EGEO was highly selective to Leishmania braziliensis and Leishmania infantum promastigotes with selective indexes of 73.66 and 71.41, respectively. EGEO did not inhibit Trypanosoma cruzi. These data suggest that the E. gracillima essential oil is a relevant source of lead compounds for development of anti-Leishmania drugs.


Assuntos
Antioxidantes/farmacologia , Antiprotozoários/farmacologia , Eugenia/química , Óleos Voláteis/farmacologia , Folhas de Planta/química , Animais , Anti-Infecciosos/análise , Antiprotozoários/química , Linhagem Celular , Leishmania/efeitos dos fármacos , Camundongos , Óxido Nítrico/metabolismo , Óleos Voláteis/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologia , Superóxidos/metabolismo , Trypanosoma cruzi/efeitos dos fármacos
9.
J Nat Prod ; 83(12): 3554-3563, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33264011

RESUMO

Structural elucidation of three new sesquiterpenoids, namely, (1Z,4E)-lepidoza-1(10),4-dien-14-ol (1), rel-(1(10)Z,4S,5E,7R)-germacra-1(10),6 diene-11,14-diol (2), and rel-(1(10)Z,4S,5E,7R)-humula-1(10),5-diene-7,14-diol (3), isolated from the liverwort Conocephalum conicum, was accomplished by a combination of extensive NMR experiments, 1H NMR simulation, and other means. Additionally, the change of the identity of bicyclogermacren-14-al, previously reported as a C. conicum constituent, to isolepidozen-14-al is proposed. Compounds 2 and 3 appear to be related to 1 via hydration involving a shared intermediate, a substituted cyclopropylmethyl cation, formed by a highly regio- and stereoselective protonation of 1, followed by a stereospecific fission of the three-membered ring. In other words, an isolepidozene derivative might be a branchpoint to humulanes and germacranes; this transformation could be of, up to now, unknown, biosynthetic and/or synthetic relevance. Multivariate statistical analysis of the compositional data of C. conicum extract constituents was used to probe the hypothesized biochemical relations. The immunomodulatory effect of 1-3 and conocephalenol (4) was evaluated in an in vitro model on both nonstimulated and mitogen-stimulated rat splenocytes. The compounds displayed varying degrees of cytotoxicity to nonstimulated splenocytes, whereas 2 and 3 were found to exert immunosuppressive effects on concanavalin A-stimulated splenocytes while not being cytotoxic at the same concentrations.


Assuntos
Adjuvantes Imunológicos/farmacologia , Hepatófitas/química , Sesquiterpenos de Germacrano/farmacologia , Adjuvantes Imunológicos/química , Estrutura Molecular , Sesquiterpenos de Germacrano/química
10.
Biol Pharm Bull ; 43(11): 1693-1698, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132314

RESUMO

Cisplatin is a widely used chemotherapy for solid tumors; however, its benefits are limited by serious nephrotoxicity, particularly in proximal tubular cells. The present study investigated the renoprotective effect and mechanisms of germacrone, a bioactive terpenoid compound found in Curcuma species on cisplatin-induced toxicity of renal cells. Germacrone (50 and 100 µM) attenuated apoptosis of human renal proximal tubular cells, RPTEC/TERT1 following treatment with 50 µM cisplatin and for 48 h. Co-treating RPTEC/TERT1 cells with cisplatin and germacrone significantly reduced cellular platinum content compared with cisplatin treatment alone. The effect of germacrone on organic cation transporter 2 (OCT2) which is a transporter responsible for cisplatin uptake was determined. Germacrone showed an inhibitory effect on OCT2-mediated methyl-4-phenylpyridinium acetate (3H-MPP+) uptake with IC50 of 15 µM with less effect on OCT1. The germacrone's protective effect on cisplatin-induced cytotoxicity was not observed in cancer cells; cisplatin's anti-cancer activity was preserved. In conclusion, germacrone prevents cisplatin-induced toxicity in renal proximal tubular cells via inhibition OCT2 transport function and reducing cisplatin accumulation. Thus germacrone may be a good candidate agent used for reducing cisplatin-induced nephrotoxicity.


Assuntos
Injúria Renal Aguda/prevenção & controle , Cisplatino/efeitos adversos , Túbulos Renais Proximais/efeitos dos fármacos , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Sesquiterpenos de Germacrano/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Células CHO , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Hep G2 , Humanos , Concentração Inibidora 50 , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/patologia , Fator 1 de Transcrição de Octâmero/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Sesquiterpenos de Germacrano/uso terapêutico
11.
Bioorg Chem ; 104: 104314, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33011538

RESUMO

Small molecule accurate recognition technology (SMART) is an emerging method for the rapid structural prediction of major constituents from crude extracts and fractions. In the present study, a targeted isolation of an Elephantopus scaber extract by SMART resulted in the obtention of 15 new (1-15) and five known germacranolide sesquiterpenes (16-20). Their structures were assigned by extensively analyzing HRESIMS, NMR, X-ray crystallographic analyses, modified Mosher's method results, and quantum chemical calculate electronic circular dichroism (ECD) spectra. All germacranolide sesquiterpenes were screened to determine their inhibitory effects with two hepatoma cell lines (HepG2 and Hep3B), and compounds 14, 16, 18, 19 and 20 showed significant cytotoxic activities against the HepG2 (IC50, 3.3-9.9 µM) and Hep3B (IC50, 4.5-8.6 µM) cell lines. Further study suggested that 18 can induce the apoptosis of hepatoma cells via mitochondrial dysfunction.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/isolamento & purificação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Relação Estrutura-Atividade
12.
J Nat Prod ; 83(11): 3230-3238, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33035058

RESUMO

Eight new germacranolides, minusolides A-H (1-8), along with two known analogues, 9 and 10, were isolated from the whole plant of Carpesium minus. Their structures were elucidated by spectroscopic analysis. Compounds 1 and 2, and 6 and 9 are two pairs of rare epimers with opposite configurations at C-2 of the 2-methylbutyryloxy group. The absolute configurations were determined by X-ray diffraction studies. Compound 7 exhibited cytotoxic activities against MDA-MB-231, A549, and HCT-116 cells with IC50 values of 6.1 ± 0.2, 8.4 ± 0.6, and 3.7 ± 0.6 µM, respectively. Compound 7 induced the apoptosis of HCT-116 cells via suppression of PARP and promoting cleavage of PARP.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Asteraceae/química , Sesquiterpenos de Germacrano/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologia , Análise Espectral/métodos
13.
Sci Rep ; 10(1): 12213, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699377

RESUMO

The intensive application of agrochemicals in crops has negatively impacted the environment and other organisms. The use of naturally occurring compounds may be an alternative to mitigate these effects. Plants are secondary metabolite reservoirs and may present allelopathic activity, which is potentially interesting to be used in bioherbicide formulations. In this context, the present work aimed to evaluate the phytotoxic and cytotoxic effects of essential oils extracted from leaves of Sparattanthelium botocudorum and Sparattanthelium tupiniquinorum in bioassays with the plant models Lactuca sativa L. and Sorghum bicolor L. Moench. The essential oils were applied at concentrations of 3,000, 1,500, 750, 375 and 187.5 ppm. Chemical characterization of the oils was performed, and their impact on the percentage of germinated seeds, initial development of L. sativa and S. bicolor seedlings, and changes in the mitotic cycle of meristematic cells from L. sativa roots was evaluated. The major compound of the essential oils was germacrene D, followed by bicyclogermacrene, ß-elemene and germacrene A. The phytotoxicity assay showed that the essential oils of both species reduced the root and shoot growth in L. sativa and decreased the germination and shoot growth in S. bicolor. Inhibition was dependent on the tested oil concentration. In the cytotoxicity assay, a decrease in mitotic index and chromosomal and nuclear alterations were observed, which resulted from aneugenic and clastogenic action.


Assuntos
Hernandiaceae/metabolismo , Óleos Voláteis/química , Plântula/efeitos dos fármacos , Compostos Orgânicos Voláteis/farmacologia , Cromatografia Gasosa , Germinação/efeitos dos fármacos , Hernandiaceae/química , Alface/efeitos dos fármacos , Alface/crescimento & desenvolvimento , Mitose/efeitos dos fármacos , Óleos Voláteis/análise , Óleos Voláteis/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Sementes/crescimento & desenvolvimento , Sesquiterpenos de Germacrano/farmacologia , Sorghum/efeitos dos fármacos , Sorghum/crescimento & desenvolvimento , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/química
14.
J Nat Prod ; 83(6): 1909-1918, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32496057

RESUMO

The need for effective candidates as cytotoxic drugs that at the same time challenge cancer multidrug resistance encouraged a search for these in plants of central Argentina. Bioassay-guided fractionation of the cytotoxic extract from Dimerostemma aspilioides led to the isolation of the germacranolide tomenphantin A (1), along with three new analogues (2-4). These efficiently inhibited the proliferation of the leukemia cell lines K562 and CCRF-CEM and their resistant variants, Lucena 1 and CEM/ADR5000, respectively, with IC50 values ranging from 0.40 to 7.7 µM. The structures and relative configurations of compounds 1-4 were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound 1 (IC50 = 0.40-5.1 µM), and, therefore, this was selected as a model for a mechanistic study, which revealed that its antiproliferative effect was mediated by cell cycle arrest in the G2/M phase followed by apoptosis. The activity of compound 1 was selective, given the absence of cytotoxicity toward peripheral blood mononuclear cells. The results show the potential of these compounds, and in particular of compound 1, as leads for the development of drug candidates to fight sensitive and resistant leukemia cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Lactonas/farmacologia , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Monócitos/efeitos dos fármacos , Componentes Aéreos da Planta/química , Extratos Vegetais/química
15.
J Nanobiotechnology ; 18(1): 86, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513194

RESUMO

Hepatic stellate cells (HSCs) were activated and secreted excessive amounts of extracellular matrix (ECM) proteins during pathogenetic progress of liver fibrosis. Germacrone (GMO) and miR-29b can play an important role in inhibiting growth of HSCs and production of type I collagen. GMO and miR-29b were co-encapsulated into nanoparticles (NPs) based on poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA). Then, NPs were modified with cyclic RGD peptides (cRGDfK). cRGDfK is an effective ligand to bind integrin αvß3 and increase the targeting ability for fibrotic liver. GMO- and miR-29b-loaded NPs exhibited great cytotoxicity to activated HSCs and significantly inhibited production of type I collagen. Liver fibrosis model of mice was induced by administration of carbon tetrachloride. Great targeting ability was achieved in liver fibrotic mice treated with cRGD-modified NPs. Significant ant-fibrotic effects have been presented based on hematoxylin and eosin (H&E), Masson and Sirius Red staining results of liver tissues collected from mice treated with drug-loaded NPs. All these results indicate GMO- and miR-29b-loaded cRGD-modified NPs have the potential for clinical use to treat liver fibrosis.


Assuntos
Cirrose Hepática/metabolismo , MicroRNAs , Nanopartículas , Peptídeos Cíclicos , Sesquiterpenos de Germacrano , Animais , Tetracloreto de Carbono/efeitos adversos , Células Cultivadas , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/química , MicroRNAs/farmacocinética , MicroRNAs/farmacologia , Nanopartículas/química , Nanopartículas/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacocinética , Sesquiterpenos de Germacrano/farmacologia , Distribuição Tecidual
16.
BMC Complement Med Ther ; 20(1): 77, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145743

RESUMO

BACKGROUND: Germacrone is an anti-inflammatory ingredient in the Chinese medicine zedoary turmeric. The purpose of this study was to explore the protective mechanism of germacrone against PC12 cells injury caused by oxygen-glucose deprivation/reperfusion (OGD/R). METHODS: OGD/R injury model of PC12 cells was established by using OGD/R (2 h/24 h). The cell viability was assessed by MTT assay and LDH release. The ultrastructure of cells was observed by transmission electron microscopy (TEM). The expression of autophagy related proteins in cells was determined by Western Blot. RESULTS: The results of ultrastructural observation showed that PC12 cells damaged by OGD/R showed typical autophagy characteristics. In addition, OGD/R observably up-regulated the expression of autophagy related proteins: the class III type phosphoinositide 3-kinase (PI3K III), light chain 3(LC3), and Beclin-1 in PC12 cells, and inhibited the expression of the class I type phosphoinositide 3-kinase (PI3K I), Protein kinase B (Akt), the mammalian target of rapamycin (mTOR), and B-cell lymphoma 2(Bcl-2) proteins. Furthermore, germacrone increased the cell viability of OGD/R-damaged PC12 cells by down-regulating the expression of LC3 protein in cells in a concentration-dependent manner. More importantly, germacrone significantly inhibited the expression of PI3K III, LC3, and Beclin-1 in OGD/R-injured PC12 cells, and up-regulated the expressionof PI3K I, Akt, mTOR, and Bcl-2 proteins in cells, and this inhibited or up-regulated effect was reversed by PI3K I inhibitor (ZSTK474). CONCLUSION: The above results indicated that germacrone could inhibit the autophagy effect in OGD/R injury model of PC12 cells, the mechanism of inhibition was regulated by PI3K III/Beclin-1/Bcl-2 and PI3K I/Akt/mTOR pathways, thereby improving the cell viability of PC12 cells and playing a neuroprotective role, which provided a new drug for the treatment of OGD/R.


Assuntos
Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão , Sesquiterpenos de Germacrano/farmacologia , Animais , Glucose/metabolismo , Estrutura Molecular , Oxigênio/metabolismo , Células PC12 , Ratos
17.
Biomed Res Int ; 2020: 7643248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32071920

RESUMO

Germacrone, a natural 10-membered monocyclic sesquiterpene with three double bonds and a ketone, was isolated from the roots of traditional Chinese medicine Saussurea costus (SC). The pharmacological value and intrinsic mechanism of germacrone in the treatment of esophageal squamous cell carcinoma (ESCC) are still unclear. Therefore, in this study, we further explored the internal molecular mechanism by which germacrone exerts its antiproliferation and antimigration ability against ESCC. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays showed that germacrone dose-dependently inhibited the proliferation of ESCC cells. Flow cytometry analysis (FACS) and wound healing experiments on germacrone treated ESCC cells showed that germacrone could induce apoptosis and inhibit the migration of ESCC cells in a dose-dependent manner. In the study on the mechanism of action of germacrone in antiesophageal cancer, we found that germacrone increased the ratio of Bax/Bcl-2 in the cytoplasm of ESCC, resulting in the activation of Caspase-9 and Caspase-3 and decreased the expression of Grp78, thereby reducing the inhibition of Caspase-12 and Caspase-7. In addition, we found that germacrone also inhibited STAT3 phosphorylation in a dose-dependent manner. In conclusion, we determined that germacrone exerted an antiesophageal effect through intrinsic apoptotic signaling pathways and by inhibiting STAT3 activity in ESCC cells.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Sesquiterpenos de Germacrano/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Proteínas de Choque Térmico/metabolismo , Humanos , Medicina Tradicional Chinesa , Fosforilação/efeitos dos fármacos , Raízes de Plantas/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo , Saussurea/química , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
18.
Comb Chem High Throughput Screen ; 23(6): 477-503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32067612

RESUMO

BACKGROUND: The parasitic protozoal infections leishmaniasis, human African trypanosomiasis, and Chagas disease are neglected tropical diseases that pose serious health risks for much of the world's population. Current treatment options suffer from limitations, but plantderived natural products may provide economically advantageous therapeutic alternatives. Several germacranolide sesquiterpenoids have shown promising antiparasitic activities, but the mechanisms of activity have not been clearly established. OBJECTIVE: The objective is to use in silico screening of known antiparasitic germacranolides against recognized protozoal protein targets in order to provide insight into the molecular mechanisms of activity of these natural products. METHODS: Conformational analyses of the germacranolides were carried out using density functional theory, followed by molecular docking. A total of 88 Leishmania protein structures, 86 T. brucei protein structures, and 50 T. cruzi protein structures were screened against 27 antiparasitic germacranolides. RESULTS: The in-silico screening has revealed which of the protein targets of Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are preferred by the sesquiterpenoid ligands.


Assuntos
Antiparasitários/farmacologia , Produtos Biológicos/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Sesquiterpenos de Germacrano/farmacologia , Antiparasitários/química , Produtos Biológicos/química , Teoria da Densidade Funcional , Avaliação Pré-Clínica de Medicamentos , Leishmania/química , Leishmania/efeitos dos fármacos , Ligantes , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Sesquiterpenos de Germacrano/química , Trypanosoma brucei brucei/química , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/química , Trypanosoma cruzi/efeitos dos fármacos
19.
Fitoterapia ; 142: 104489, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32004654

RESUMO

Influenza virus is one of the most widespread infectious diseases in the world. It poses a serious public health threat to humans. With the emergence of drug-resistant virus strains, antiviral drugs are urgently needed to control virus transmission and disease progression. In this study, three main active substances-curcumol, curdione and germacrone-were isolated from the traditional Chinese medicine zedoary. They inhibited the replication of influenza A (H1N1) virus in a dose-dependent manner. After treatment with these compounds, the expression of viral protein and RNA synthesis were inhibited. In vivo, these compounds also reduced H1N1-induced lung damage and the load of virus in serum as well as whole blood cells. In a proteomic analysis, after treatment with germacrone, the expression of antiviral protein and the amount of intracellular virus were significantly reduced, further proving that germacrone can inhibit viral replication. Our experiments have shown that curcumol, curdione and germacrone can inhibit the replication of H1N1 virus; in particular, germacrone shows potential both in vitro and in vivo as a therapeutic drug.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Sesquiterpenos de Germacrano/farmacologia , Sesquiterpenos/farmacologia , Células A549 , Animais , Proliferação de Células , Medicamentos de Ervas Chinesas , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óleos/química , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Sesquiterpenos/química , Sesquiterpenos de Germacrano/química , Organismos Livres de Patógenos Específicos
20.
BMC Complement Med Ther ; 20(1): 21, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-32020876

RESUMO

BACKGROUND: Germacrone is one of the natural bioactive compounds found in Rhizoma curcuma essential oils. In this study, the potential anti-cancer effect of germacrone in gastric cancer cell line BGC823 was investigated. METHODS: The cell viability and proliferative activity were assessed, and cell cycle analysis was also performed. Hoechst 33258 and Annexin V/PI double staining was used for detection of cell apoptosis. Protein profiles of cell cycle-related and apoptosis-related proteins were assessed. RESULTS: MTT assay revealed that germacrone had marked cytotoxicity on BGC823 cells. Germacrone induced cell cycle arrest in the G2/M phase via remarkably decreased expression levels of cyclin B1, cdc 2 and cdc 25c. In addition, the treatment with germacrone induced caspase-3 activity and PARP cleavage. These findings demonstrated the effects of germacrone on inhibiting cell proliferation through induction of G2/M phase cell cycle arrest and promotion of cell apoptosis. It also indicated that germacrone functioned through modulations of cell cycle-associated protein expression and mitochondria-mediated apoptosis. CONCLUSION: These findings will be valuable as the molecular basis for the germacrone-mediated anti-cancer effect against gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Óleos Voláteis/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Neoplasias Gástricas/patologia , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Neoplasias Gástricas/tratamento farmacológico
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